9 research outputs found
Novel highly potent CD4bs bNAb with restricted pathway to HIV-1 escape
Purpose: Broadly HIV-1 neutralizing antibodies (bNAbs) can suppress viremia
in humans and represent a novel approach for effective immunotherapy.
However, bNAb monotherapy selects for antibody-resistant viral variants.
Thus, we focused on the identification of new antibody combinations and/or
novel bNAbs that restrict pathways of HIV-1 escape.
Methods: We screened HIV-1 positive patients for their neutralizing
capacities. Following, we performed single cell sorting and PCR of HIV-1
Env-reactive mature B cells of identified elite neutralizers. Found antibodies
were tested for neutralization and binding capacities in vitro. Further, their
antiviral activity was tested in an HIV-1 infected humanized mouse model.
Results: Here we report the isolation of antibody 1–18, a VH1–46-encoded
CD4 binding site (CD4bs) bNAb identified in an individual ranking among the
top 1% neutralizers of 2,274 HIV-1-infected subjects. Tested on a 119-virus
panel, 1–18 showed to be exceptionally broad and potent with a coverage of
97% and a mean IC50 of 0.048 lg/mL, exceeding the activity of most potent
CD4bs bNAbs described to-date. A 2.4 Å cryo-EM structure of 1–18 bound to a
native-like Env trimer revealed that it interacts with HIV-1 env similar to other
CD4bs bNAbs, but includes additional contacts to the V3 loop of the adjacent
protomer. Notably, in vitro, 1–18 maintained activity against viruses carrying
mutations associated with escape from VRC01-class bNAbs. Further, its HIV-1
env wide escape profile differed critically from other CD4bs bNAbs. In
humanized mice, monotherapy with 1–18 was sufficient to prevent the
development of viral escape variants that rapidly emerged during treatment
with other CD4bs bNAbs. Finally, 1–18 overcame classical HIV-1 mutations
that are driven by VRC01-like bNAbs in vivo.
Conclusion: 1–18 is a highly potent and broad bNAb that restricts escape and
overcomes frequent CD4bs escape pathways, providing new options for bNAb
combinations to prevent and treat HIV-1 infection
Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site
HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-angstrom- and 3.9-angstrom-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs. Env trimer was complexed with 10-1074 (against the V3-loop) and IOMA, a new CD4-binding site (CD4bs) antibody. Although IOMA derives from VH1-2*02, the germline gene of CD4bs-targeting VRC01-class bNAbs, its light chain lacks the short CDRL3 that defines VRC01-class bNAbs. Thus IOMA resembles 8ANC131-class/VH1-46 derived CD4bs bNAbs, which have normal-length CDRL3s. The existence of bNAbs that combine features of VRC01-class and 8ANC131-class antibodies has implications for immunization strategies targeting VRC01-like bNAbs
Antibody 10-1074 suppresses viremia in HIV-1-infected individuals
Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 logic copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection